There is increasing evidence that antibodies targeting the CD4 induced (CD4i) epitopes on the HIV envelope spike can facilitate control of viremia and quite possibly protection from transmission after exposure (reviewed in (1, 2)). We have developed a gp120 based immunogen that induces responses that target these highly conserved regions called the Full Length Single Chain (FLSC). In rhesus macaques, a FLSC molecule derived from HIV (BaL) induced immune responses that target these CD4i epitopes and protect against a rectal heterologous challenge in 2 independent studies, one published (3) and another unpublished. Our next challenge is to develop a vaccine which will induce a sustainable immune response. For envelope based vaccines developed thus far, the antibody response is generally not sustained for more than 4 months (reviewed in (4)). Without continued boosting, any protection observed after an initial exposure would wane, making a recent vaccinee susceptible under repeat exposures. To meet this challenge, we propose a co formulation with the Tat toxoid, a biologically inactive but highly immunogenic form of Tat (5-7). Extracellular Tat protein that is released from acutely infected cells causes the suppression of the T cell immune responses including key helper responses that support the induction of antibodies (reviewed in (8, 9). We would propose that inducing an antibody response that would inactivate and clear this extracellular Tat would protect humoral responses to the FLSC. The result would be the sustained production of CD4i antibodies that would protect against multiple challenges. Consequently, our hypothesis is that combining biologically inert but still immunogenic Tat ("Tat Toxoid") with FLSC will prolong and increase protective antibodies induced by FLSC in the face of repeated challenge. We propose to test this hypothesis through the following aims: Aim 1. Assess the efficacy provided by the FLSC/Tat toxoid co-administration against rectal challenge with SHIV162p3. Aim 2. Determine if the co-administration with Tat toxoid improves the quantity and sustainability of envelope specific cellular responses and CD4i directed antibody responses before and after challenge. If successful, we will use the data generated by these studies to support further clinical evaluation of the proposed vaccine candidate. Of course, a successful vaccine against HIV would have an enormous global impact on AIDS and AIDS related malignancies. PUBLIC HEALTH RELEVANCE: Our goal is to evaluate in a rhesus macaque SHIV model whether a combination of the Full Length Single Chain (FLSC) and Tat toxoid can potentially be preventative vaccine for AIDS and AIDS malignancies.